CART peptides are neurochemical messengers in the brain that are involved in drug addiction, and they may be especially relevant to psychostimulants like cocaine and methamphetamine. Indeed, administration of cocaine or amphetamine to animals results in rapid upregulation of CART mRNA. Also, when CART peptides are injected into the brain, the animals behave as though they have been given psychostimulants. Locomotor activity increases and they produce signs of being dependent. Because CART peptides are naturally occurring mediators and modulators of these drugs, and because they may make good targets for new medications, they must be well understood. This proposal focuses on the brain mechanisms that control the levels of these peptides. In particular, the research will produce an understanding of how the CART gene is regulated by cellular events such as stimulation by drug and signal transduction pathways. The CART gene "promoter," which regulates expression of the gene and ultimately the level of its peptide product, will be characterized.